Ibuprofen-loaded calcium phosphate granules: A new bone substitute for local relieving symptoms of osteoarthritis.

Musculoskeletal diseases often demand a drug treatment at the specific site of injury or defect site. In this context, the use of calcium phosphates is attractive as it allows both the bone substitution and the local delivery of a drug substance. In this work, we present a drug delivery device that combines calcium phosphate bioceramic granules and ibuprofen, a widely used anti-inflammatory drug. After verifying in vitro biocompatibility of the ibuprofen-loaded calcium phosphate granules on murine preosteoblastic cells (MC3T3), we evaluated in vitro efficiency of the drug substance released from the bioceramic using rheumatoid arthritis synoviocytes. Our data document that ibuprofen-loaded calcium phosphate granules reduced inflammatory response and increased apoptosis of synoviocytes. In vivo study showed that both unloaded, and ibuprofen-loaded calcium phosphate granules induced a progressive osteogenesis, but in the case of ibuprofen-loaded implants, bone ingrowth was more limited in first weeks. However, as far as concerns inflammation, while unloaded granules showed inflammation up to 4 weeks, ibuprofen loaded granules did not show any significant inflammation. Ibuprofen concentration determination in blood samples showed that a very small amount of the drug reached the general circulation which render this drug delivery system suitable for both bone substitution and reduction of inflammation at the implantation site. Thus, this new drug carrier could be used to locally relieve inflammatory bone diseases symptoms including rheumatoid arthritis but, beyond this study, this kind of granules could be considered for the delivery of therapeutic agents such as antibiotic, analgesic or anticancer drugs.

Investigation of the Compressibility and Compactibility of Titanate Nanotube-API Composites.

The present work aims to reveal the pharma-industrial benefits of the use of hydrothermally synthesised titanate nanotube (TNT) carriers in the manufacturing of nano-sized active pharmaceutical ingredients (APIs). Based on this purpose, the compressibility and compactibility of various APIs (diltiazem hydrochloride, diclofenac sodium, atenolol and hydrochlorothiazide) and their 1:1 composites formed with TNTs were investigated in a comparative study, using a Lloyd 6000R uniaxial press instrumented with a force gauge and a linear variable differential transformer extensometer. The tablet compression was performed without the use of any excipients, thus providing the precise energetic characterisation of the materials' behaviour under pressure. In addition to the powder functionality test, the post-compressional properties of the tablets were also determined and evaluated. The results of the energetic analysis demonstrated that the use of TNTs as drug carriers is beneficial in every step of the tabletting process: besides providing better flowability and more favourable particle rearrangement, it highly decreases the elastic recovery of the APIs and results in ideal plastic deformation. Moreover, the post-compressional properties of the TNT⁻API composites were found to be exceptional (e.g., great tablet hardness and tensile strength), affirming the above results and proving the potential in the use of TNT carriers for drug manufacturing.

ß-TCP porous pellets as an orthopaedic drug delivery system: ibuprofen/carrier physicochemical interactions.

Calcium phosphate bone substitute materials can be loaded with active substances for in situ, targeted drug administration. In this study, porous ß-TCP pellets were investigated as an anti-inflammatory drug carrier. Porous ß-TCP pellets were impregnated with an ethanolic solution of ibuprofen. The effects of contact time and concentration of ibuprofen solution on drug adsorption were studied. The ibuprofen adsorption equilibrium time was found to be one hour. The adsorption isotherms fitted to the Freundlich model, suggesting that the interaction between ibuprofen and ß-TCP is weak. The physicochemical characterizations of loaded pellets confirmed that the reversible physisorption of ibuprofen on ß-TCP pellets is due to Van der Waals forces, and this property was associated with the 100% ibuprofen release.

Comparison of three dissolution apparatuses for testing calcium phosphate pellets used as ibuprofen delivery systems.

Porous calcium phosphate pellets were produced according to two granulation processes (low and high shear wet granulations) and drug loaded with five ibuprofen contents (1.75%, 7%, 12.5%, 22%, and 36%) in order to ensure both bone defect filling and local drug delivery. The drug-release kinetics from the two types of pellets was studied using three dissolution apparatuses: paddle apparatus, reciprocating cylinder, and flow-through cell. The paper compared the three dissolution methods and considered the effect of the granulation process on the ibuprofen-release kinetics. Dissolution data were analyzed using the Weibull function as well as the difference (f1) and similarity (f2) factors. Dissolution kinetics was not influenced by the granulation process, regardless of the dissolution apparatus and of the drug content. The comparison of the three dissolution devices indicated that ibuprofen was released faster from granules loaded with 36% of drug content with the reciprocating apparatus, due to the disintegration of the granules occurring during the dissolution test. For the other drug contents, dissolution profiles were not significantly different from one apparatus to another. However, the flow-through cell seemed to be more suitable for the drug-release study of implantable materials.

Dissolution of a surfactant-containing active porous material.

We have studied the imbibition and dissolution of a porous material in two separate scenarios: (1) when the porous material contains a surfactant powder and (2) when the porous material is dissolved in a surfactant solution. We show that the dissolution kinetics in both scenarios is significantly affected by the presence of the surfactant and results in an increase in the characteristic imbibition time of the porous material, which can be well understood in the framework of the classical law of capillarity. Slowing of the imbibition kinetics was found to be affected by a modification of the liquid wetting properties, but is also affected by a variation in the solubility of the porous material in the presence of the surfactant. Furthermore, there is a depletion effect of the surfactant inside the rising liquid, which is in good agreement with previous work and theoretical predictions.

Fabrication of porous substrates: a review of processes using pore forming agents in the biomaterial field.

This paper is a review of solid and casting manufacturing processes able to create porous materials, mainly in the biomaterial field. The considered methods are based on pore forming agents that are removed either by heating or by dissolution. All techniques lead to products presenting pores with amount, size, and shape are close to those of the initial pore formers. Porosities up to 90% with pores ranging from 1 to 2000 microm are reported. Major differences concern macrointerconnections that are more frequently obtained using foams, or porogens which undergo a melting stage during firing. Casting methods combined with solid free form fabrication are promising for the design of porous network through the manufacturing of 3D scaffolds corresponding to the desired porosity.

Quality of phenobarbital solid-dosage forms in the urban community of Nouakchott (Mauritania).

PURPOSE: Epilepsy is a major public-health problem in Africa. The quality of available drugs is a limiting factor for an adequate management. The aim of this study was to describe the proportion of poor-quality phenobarbital (PB) solid-dosage forms and evaluate the factors associated with its quality in Nouakchott (Mauritania). METHODS: A cross-sectional study was carried out within pharmacies, hospitals, and on the parallel market in March 2003. PB samples were bought by a native person and then assayed by a liquid chromatography method. A package was considered to be of good quality if the active-substance average content was between 85 and 115% of the stated content printed on the packet. RESULTS: Forty-five pharmaceutical stores were visited, enabling us to collect 146 samples of PB. Three brand names were available in Nouakchott. They originated from France, Morocco, Senegal, and Egypt. Results: A prevalence of 13.7%[95% confidence interval (CI), 8.8-20.0] of poor-quality PB was found. All samples from Morocco were underdosed. The generic active content was satisfactory, but saccharose, an excipient with a potential side effects, was identified. Two factors associated with the good quality of PB have been put forward: tablets manufactured in France and loose packaging as generics conditioned in such a way were of good quality. CONCLUSIONS: This study shows that the quality of antiepileptic drugs in Africa is still worrying. The setting up of medicine quality control in Mauritania is legitimate. Considering the good quality of generic PB and its lower cost, this type of medicine should be promoted in this region.

Powder functionality test: a methodology for rheological and mechanical characterization.

In most pharmaceutical formulations, the part of the excipients, in quantity and number, is larger than that of active principles, justifying particular attention to their characteristics to ensure quality, efficacy, and reproducibility of final forms. Whereas chemical specifications are described in Pharmacopeias, physical characteristics, up to now, have not been sufficiently considered. Nevertheless, there is a need for tests to objectively compare technological performances of products and justify composition of medicinal products. The powder functionality test described in this article is based on the analysis of the global behavior of materials under pressure. The powder compression is performed using an instrumented uniaxial press, Lloyd 6000R, and a compression cell of 1 cm3 in volume, allowing a complete and early characterization with a few grams of material. Indices characterizing packing, densification energies, energetic yields, and deformation mode of the particles are proposed from the analysis of compression cycles. Cohesion and energy of rupture are deduced from the diametral rupture cycles of the compacts. Application of this methodology to supplied celluloses has shown better flow properties of microcrystalline celluloses due to their higher bulk density and particle size. The energy fraction lost as frictions is very important and independent of the type of celluloses, whereas elastic energy is higher for powdered celluloses P100 and G250. Finally the efficacy to convert compaction energy into cohesion is higher for products with a small degree of polymerization, i.e., microcrystalline celluloses, except A301 and A302, which also are distinguished by their low porosity.